A prominent feature of multiple myeloma (MM) and other malignancies is significant genomic instability leading to genetic changes which ultimately result in acquisition of drug resistance and progression of disease. In the previous funding period, we evaluated telomerase as a target in MM, and have conducted a first-in-human study evaluating telomerase inhibitor in MM. Our in vitro and in vivo evaluations have shown that homologous recombination (HR) provides an alternative pathway to maintain telomeres and overcome effects of telomerase inhibition. We have further evaluated the role of HR in MM, and observed that HR activity is significantly higher in MM cells compared to normal plasma cells; and plays a significant role in acquisition of new genomic changes overtime, as demonstrated using various methods including: copy number alteration by array CGH, new translocations using paired end sequencing, and acquisition of novel mutations using whole genome sequencing of paired samples. Importantly, we have observed that inhibition of HR activity reduces acquisition of new genetic changes; and conversely, that induction of HR leads to increased genetic instability in MM, associated with the development of drug resistance. Our emerging focus of investigation therefore has been to define the molecular basis of these evolving genetic changes, and to devise strategies to suppress genomic evolution to make tumor cells static, thereby maintaining sensitivity to therapy. We have now focused our attention on understanding the role of nucleases, a key component of HR and observed elevated endonuclease activity in MM and demonstrated that knock-down of AP endonuclease leads to inhibition of HR and reduction in the rate of new mutations and conversely induction of AP endonuclease induces genomic instability and transformation of normal cells. Based on these preliminary data, we hypothesize that elevated nuclease activity mediates DNA instability in MM and may therefore contribute to the development of drug resistance and disease progression. To this end, we will pursue the following specific aims: Specific Aim 1: To evaluate the role of elevated nuclease activity, a key mediator of genomic instability, as a marker of prognosis Specific Aim 2: To evaluate the molecular consequences of elevated nuclease activity in normal and MM cells. Specific Aim 3: To develop small molecule inhibitors of endonuclease using a high-throughput, cell-based, phenotypic screen to prevent evolution of genomic changes and progression in MM. The proposed studies will improve our understanding of genomic progression in MM and may facilitate the development of prognostic tests for disease progression, as well as identify novel therapeutic strategies to prevent evolution of the disease and development of drug resistance. The principles and agents identified here will be applicable to a majority of other malignancies.